Modulation of neural stem/progenitor cell proliferation during experimental Herpes Simplex encephalitis is mediated by differential FGF-2 expression in the adult brain

Abstract

Neural stem cells (NSCs) respond to inflammatory cues induced during brain injury and are thought to be involved in recovery from brain damage. Little is known about NSC response during brain infections. The present study evaluated NSC proliferation during Herpes Simplex Virus-1 brain infection. Total numbers of nestin(+) NSCs increased significantly in infected brains at 6 d post infection (p.i.). However, by 15 d p.i. the nestin(+) population decreased significantly below levels observed in uninfected brains and remained depressed through 30 d p.i.. This initial increase in NSC population occurred concurrently with increased brain cell proliferation, which peaked at 3 d p.i.. On closer examination, we found that while actively proliferating Sox2(+) NSCs increased in number at 6 d p.i., proliferating DCX(+) neuroblasts contributed to the increased response at 3 d p.i.. However, overall proliferation decreased steadily from 15 d p.i. to below control levels. To determine the mechanisms involved in altering NSC proliferation, neurotrophin and growth factor expression profiles were assessed. FGF-2 gene expression increased at 5 d p.i. and was robustly down-regulated at 15 d p.i. (>1000 fold), which was further confirmed by increased FGF-2 immunostaining around the lateral ventricles. Furthermore, supplementing infected animals with recombinant FGF-2, at 15 d p.i., significantly increased the number of proliferating brain cells. These findings demonstrate that the temporal changes in NSC proliferation are mediated through the regulation of FGF-2 and that the NSC niche may benefit from supplementation with FGF-2 during HSV-1 brain infection.

Microglia‐induced IL‐6 protects against neuronal loss following HSV‐1 infection of neural progenitor cells

“…Based on this observation, we hypothesized NPCs may be vulnerable to HSV-1 either by direct cytopathic effect or alternatively, by altering the population of differentiated progeny cells. Consistent with this hypothesis, a recent study reported intranasal infection with HSV-1 led to an initial rise then subsequent decrease in transplanted nestin 1 NSCs in the brain of mice (Rotschafer et al, 2013). In fact, we found ocular infection with HSV-1 led to a FIGURE 11: Neutralization of IL-6 blocks microglia-induced preservation of neuroblasts.…”

“…I n vitro models suggested MG and MG-CM could direct NPC migration and facilitate the differentiation of NPC toward a neuronal phenotype (Aarum et al, 2003; Walton et al, 2006). In contrast, the analysis of in vivo models using HSV-1 have led some to suggest MG activation along with leukocyte infiltration contribute to the neuropathology of HSE (Marques et al, 2008) including a detrimental outcome to NPC maintenance (Rotschafer et al, 2013). Our data support a beneficial role of MG in maintaining the neuronal phenotype of NPC cultures challenged with HSV-1.…”

Resident T Cells Are Unable To Control Herpes Simplex Virus-1 Activity in the Brain Ependymal Region during Latency

“…As the SVZ is proximal to the lateral ventricles and NPCs are infected during HSE (8), it is tempting to speculate the neurologic deficits observed in the majority of surviving HSE patients are due to the simmering HSV lytic infection that alters environmental cues of NPC differentiation within the EP as a result of the host anergic T cell response to infection. To this end, experimental evidence suggests latent HSV-1 infection does alter NPC proliferation as a result of FGF2 deficits (90) resulting in behavioral changes in mice (10). …”

Defining nervous system susceptibility during acute and latent herpes simplex virus-1 infection

“…This same study also found under conditions that drive NPC differentiation, there is a predilection in blocking neuroblast development without any obvious effect on astrocyte or oligodendrocyte differentiation. This phenotype was recapitulated in vivo where NPC numbers were reduced during the peak of viral encephalitis following both ocular and intranasal infection (Chucair-Elliott, Conrady, 2014, Rotschafer et al, 2013). Since experimental animal models have demonstrated viral tropism towards cortical tissue surrounding the lateral ventricles and hippocampus, these findings correlate with the involvement of similar tissue during human encephalitis.…”